Multiple sclerosis (MS) is a common neurological disorder with a significant genetic component. The long-term goal our research is to identify the underlying susceptibility genes in MS. The initial goal of this proposal is to screen for linkage of MS to markers spanning the entire human genome. We will combine efficient PCR-based marker genotyping with state-of-the-art statistical analysis using a multianalytical approach to achieve this goal. We have identified and sampled 55 families with multiple cases of MS. The families will be analyzed using a multi-analytical approach that includes sibpair (SP), affected pedigree member (APM), and lod score analyses. A set of specific screening criteria have been outlined that will maximize our chances of identifying chromosomal regions carrying susceptibility genes while rapidly eliminating false positive results. The promising chromosomal regions will be followed-up by more detailed statistical analysis, genotyping of additional markers in the region, and genotyping a second, independent dataset. If all these tests confirm that a susceptibility gene lies within the region, we will start more detailed polymorphism studies of this region. In order to further enhance our screening and follow-up process, we will test new statistical analytical techniques currently under development by our collaborators, such as two-trait locus, TDT, and WPC techniques. We will perform detailed studies of the power of these analytical methods by applying them to simulated data that approximates realistic agenetic models of MS, inclusive of multiple genes, and polygenic and environmental components. We are encouraged by our preliminary data, which has excluded several chromosomal region, and identified one promising region on chromosome 19 which we have started to follow-up. The combination of clinical, genetic epidemiological, and molecular expertise represented in this group investigators, and our commitment to MS make this approach a viable method for dissecting the genetic etiology of ms.